This proposal is from Dr. Linda Sandell, a cartilage biologist in the Department of Orthopaedic Surgery and Dr. Jim Cheverud, a population geneticist in the Department of Anatomy and Neurobiology. We propose to identify genetically defined mouse models of cartilage healing. Recently, a direct correlation between articular cartilage healing and protection from osteoarthritis (OA) has been demonstrated. This will be a large-scale project that creates a unique resource for the study of the genes that contribute to cartilage healing and thus to OA. Dr. Cheverud currently uses "super-healing" mice for studies on genes that contribute to body size and has developed 12 inbred strains of mice containing portions of the genome and an advanced intercross between large (healing) and small (non-healing) mice of 40 generations. It has been demonstrated that the parental "super-healing" mice are able to regenerate cartilage significantly better than control mice. In the Department of Orthopaedic Surgery, we have established mouse models of fracture healing, cartilage healing and ligament healing and will perform full thickness cartilage wounds in the test animals. The collaboration between the Departments of Anatomy and Neurobiology and Orthopaedic Surgery would provide a unique multi-disciplinary team approach to the problem of cartilage repair. We are in a unique position to carry out these studies provided substantial special funding can be obtained. These studies will provide a completely new resource to investigators in the field and provide the resources to understand the genetics of cartilage repair. These animal models with defined genetics would be made available to investigators to study the mechanism of how a specific gene, or group of genes, contribute to cartilage repair and thus to OA. An investment in this area will catapult the field to allow for the understanding of cartilage repair, a field that, without this Grand Opportunity, will otherwise remain dormant in that funding for the "one strain at a time" approach will not be available. The results found in mice, a species that is amenable to genetic studies, will be immediately applicable to the human disease as many of the genes are likely to be the same or affect the same pathway. Long term, understanding of the genes that contribute to cartilage healing may allow for the "intrinsic" repair of cartilage long before OA develops to the point of cartilage degeneration. Knowledge of the players involved in sustaining a cartilage repair response will allow us to determine which individuals will be more susceptible to OA. This could have a huge public health impact as the pain and disability from OA is estimated to effect 40 million people and cost 3 billion dollars per year in work loss and special care.